Significance Hypoglycemia is major clinical problem in insulin-treated diabetes. Hypoglycemia limits the ability of patients to maintain adequate control blood of glucose levels in order to prevent the devastating complications of diabetes. Increased glucagon secretion is a primary defense against hypoglycemia, but glucagon responses to hypoglycemia are impaired in diabetes. The etiology of the impairment is poorly understood, but may involve a failure of the autonomic nervous system (ANS) to stimulate glucagon secretion since the ANS contributes to this response several species. However, the role of the ANS in humans has been controversial. Objectives To investigate the importance of the ANS in hypoglycemia-induced glucagon secretion and the role of ANS deficits in impaired responses in a primate model of diabetes. Results We investigated the ANS contribution to hypoglycemia-induced glucagon secretion using two pharmacological approaches (blockade of ganglionic neurotransmission with trimethaphan or ANS receptor blockade) to impair the ANS inputs to the pancreas in conscious rhesus macaques. We found that the ANS has a major role in mediating the glucagon response during hypoglycemia of 2.0 mmol/L. Based on these results, we have conducted a study in human subjects and found a similar autonomic contribution to hypoglycemia-induced glucagon secretion in humans. The nonhuman primate studies provided crucial background and methodological information for the human studies. Future Directions We are now examining the autonomic regulation glucagon secretion during hypoglycemia and its impairment in monkeys with experimental diabetes induced by streptozotocin administration as a model to investigate interventions that may prevent the impairment of hypoglycemia-induced glucagon secretion. KEY WORDS hypoglycemia, glucagon, autonomic nervous system, diabetes FUNDING NIH DK50129 PUBLICATIONS Taborsky, Gerald J, Ahren, Bo, and Peter J. Havel. Autonomic Mediation of Glucagon Secretion During Hypoglycemia Implications for Impaired A-Cell Responses in Type-1 Diabetes, Perspective in Diabetes, Diabetes 47 995-1005, 1998.